This invention is directed to the use of non-steroidal anti-inflammatory agents, and especially certain non-steroidal cyclooxygenase inhibitors in combination with prostaglandin FP receptor agonists for treating glaucoma and/or ocular hypertension in an individual.
The glaucomas are a heterogeneous group of optic neuropathies characterized by cupping of the optic nerve head, thinning of the retinal nerve fiber layer due to loss of retinal ganglion cells, and specific pathognomonic changes in visual fields. Elevated intraocular pressure (IOP) is a very important risk factor for the development of most common forms of glaucoma (Sommer A, et al., xe2x80x9cRelationship Between Intraocular Pressure and Primary Open Angle Glaucoma Among White and Black Americans,xe2x80x9d Arch. Ophthalmol, 109:1090-1095 (1991)).
A family history of glaucoma also is an important risk factor for the development of glaucoma. It appears that a significant portion of glaucoma is inherited (or at least the risk for developing glaucoma is inherited) although it is often difficult to establish clear inheritance patterns for most of the glaucomas because of the disease onset late in life and the slowly progressive clinical manifestations of the disease. Despite these problems, a number of families with heritable forms of glaucoma have been identified and these families have been used to map a variety of glaucoma genes (Sheffield, et al., xe2x80x9cGenetic Linkage of Familial Open Angle Glaucoma to Chromosome 1q21-q31,xe2x80x9d Nature Genetics, 4:47-50 (1993); Sarfarazi, et al., xe2x80x9cAssignment of a Locus (GLC3A) for Primary Congenital Glaucoma (Buphthalmos) to 2p21 and Evidence for Genetic Heterogeneity,xe2x80x9d Genomics, 30:171-177 (1995); Akarsu, et al., xe2x80x9cA Second Locus (GLC3B) for Primary Congenital Glaucoma (Buphthalmos) Maps to the 1p36 Region,xe2x80x9d Human Molecular Genetics, 5(8):1199-1203 (1996); Stoilova, et al., xe2x80x9cLocalization of a Locus (GLC1B) for Adult-Onset Primary Open Angle Glaucoma to the 2cen-q13 Region,xe2x80x9d Genomics, 36:142-150 (1996); Wirtz, et al., xe2x80x9cMapping a Gene for Adult-Onset Primary Open-Angle Glaucoma to Chromosome 3q,xe2x80x9d Am. J. Hum. Genet., 60:296-304 (1997); Andersen, et al., xe2x80x9cA Gene Responsible for the Pigment Dispersion Syndrome Maps to Chromosome 7q35-q36,xe2x80x9d Arch. Ophthalmol., 115:384-388 (1997). The first glaucoma gene mapped (GLC1A) was in a large family with autosomal dominant inherited juvenile glaucoma (JG). This disease is characterized by an early disease onset (at the age of late teens to early 20s), relatively high IOPs, and general resistance to conventional pharmacological IOP lowering therapy. The GLC1A gene was mapped by positional cloning and linkage analysis to chromosome 1q22-q25 (Sheffield et al, Id., and a number of other groups have confirmed the 1q location of this juvenile glaucoma gene (Richards, et al., xe2x80x9cMapping of a Gene for Autosomal Dominant Juvenile-Onset Open-Angle Glaucoma to Chromosome 1q,xe2x80x9d Am. J. Hum. Genet., 54:62-70 (1994); Morissette, et al., xe2x80x9cA Common Gene for Juvenile and Adult-Onset Primary Open-Angle Glaucomas Confined on Chromosome 1q,xe2x80x9d Am. J. Hum. Genet., 56:1431-1442 (1995); Wiggs, et al., xe2x80x9cGenetic Linkage of Autosomal Dominant Juvenile Glaucoma to 1q21-q31 in Three Affected Pedigrees,xe2x80x9d Genomics, 21:299-303 (1994); Meyer, et al., xe2x80x9cAge-Dependent Penetrance and Mapping of the Locus for Juvenile and Early-Onset Open-Angle Glaucoma on Chromosome 1q (GLC1A) in a French Family,xe2x80x9d Hum. Genet., 98:567-571 (1996); Graff, et al., xe2x80x9cConfirmation of Linkage to 1q21-31 in a Danish Autosomal Dominant Juvenile-Onset Glaucoma Family and Evidence of Genetic Heterogeneity,xe2x80x9d Hum. Genet., 96:285-289 (1995). Glaucoma due to the GLC1A gene is hereinafter referred to as GLC1A glaucoma or 1q glaucoma.
The GLC1A gene was identified as encoding a 57 kD protein expressed in the trabecular meshwork (TM) (Stone, et al., xe2x80x9cIdentification of a Gene That Causes Primary Open Angle Glaucoma,xe2x80x9d Science, 275:668-670 (1997). The expression of the GLC1A gene, and the encoded TM protein, is up-regulated by glucocorticoids (Polansky, et al., xe2x80x9cIn Vitro Correlates of Glucocorticoid Effects on Intraocular Pressure,xe2x80x9d Glaucoma Update IV (1991); and Polansky, et al., xe2x80x9cCellular Pharmacology and Molecular Biology of the Trabecular Meshwork Inducible Glucocorticoid Response Gene Product,xe2x80x9d Ophthalmologica, 211:126-139 (1997). This TM protein is also known as TIGR (trabecular meshwork inducible glucocorticoid response) (Polansky, Id.). The glucocorticoid-induction of this TM protein has been suggested to be involved in the generation of glucocorticoid-induced ocular hypertension and glaucoma (Polansky, Id.).
The GLC1A gene is expressed in other ocular tissues such as the ciliary epithelium (Ortego, et al., xe2x80x9cCloning and Characterization of Subtracted cDNAs from a Human Ciliary Body Library Encoding TIGR, a Protein Involved in Juvenile Open Angle Glaucoma with Homology to Myosin and Olfactomedin,xe2x80x9d FEBS Letters, 413:349-353 (1997) and the retina (Kubota, et al., xe2x80x9cA Novel Myosin-like Protein (Myocilin) Expressed in the Connecting Cilium of the Photoreceptor: Molecular Cloning, Tissue Expression, and Chromosomal Mapping,xe2x80x9d Genomics, 41:360-369 (1997). The gene is referred to by several names including GLC1A (Sheffield, supra; Sunden, et al., xe2x80x9cFine Mapping of the Autosomal Dominant Juvenile Open Angle Glaucoma (GLC1A) Region and Evaluation of Candidate Genes,xe2x80x9d Genome Research, 6:862-869 (1996); Stone, et al., supra, TIGR (Polansky supra; Ortego, supra, and myocilin (Kubota, supra). Mutations inGLC1A are not only responsible for juvenile glaucoma, but also a significant subset of adult onset primary open angle glaucoma (Stone, et al., supra); Adam, et al., xe2x80x9cRecurrent Mutations in a Single Exon Encoding the Evolutionarily Conserved Olfactomedin-Homology Domain of TIGR in Familial Open-Angle Glaucoma,xe2x80x9d Human Molecular Genetics, 6(12):2091-2097 (1997). The 1q glaucoma gene (GLC1A) is the subject of Nguyen, et al., U.S. Pat. No. 5,606,043, issued Feb. 25, 1997.
Ocular inflammation is a condition which generally affects the patient with scratchiness, itchiness and/or red eye. Ocular inflammation can be initiated by various insults. For example, ocular inflammation can result from allergic response to various allergens, trauma to the eye, dry eye and surgical complications. Various anti-inflammatory therapies are currently known for the treatment of inflammation, including the topical administration of non-steroidal anti-inflammatory agents such as diclofenac for ophthalmic inflammation. A number of these therapies, from aspirin to the recently commercialized COX II inhibitors, celocoxib and refocoxib, are believed to involve, at least in part, inhibition of prostaglandin synthesis. In addition to the treatment of inflammation, several patent applications have disclosed the use of non-steroidal cyclooxygenase inhibitors to treat intraocular pressure (WO 95/17178) through the action of the compounds on trabecular meshwork cells (WO 96/40103 and WO 96/40102). At least some of the beneficial effects of the non-steroidal cyclooxygenase inhibitors are attributed to the inhibition of the expression of myocilin (or TIGR) which is the gene product of GLC1A.
It is known that trabecular meshwork cells have glucocorticoid receptors and that glucocorticoid binding with these receptors causes a change in trabecular meshwork cell gene expression. Known manifestations of this change include a reorganization of the cytoskeleton (Wilson, et al., xe2x80x9cDexamethasone Induced Ultrastructural Changes in Cultured Human Trabecular Meshwork Cells, Cur. Eye Res., 12:783-793 (1993), and Clark, et al., xe2x80x9cGlucocorticoid-Induced Formation of Cross-Linked Actin Networks in Cultured Human Trabecular Meshwork Cells,xe2x80x9d Invest. Ophthalmol. Vis. Sci., 35:281-294 (1994) and increased deposition of the extracellular matrix material in trabecular meshwork cells. As a result, the trabecular meshwork becomes xe2x80x9ccloggedxe2x80x9d and unable to perform one of its most critical functions, that is, serving as a gateway for aqueous humor flow from the anterior chamber of the eye. When the aqueous humor flow out of the eye via the trabecular meshwork is diminished, the intraocular pressure of the eye rises. If this state of elevated intraocular pressure (IOP) is maintained or frequently occurs, the optic nerve head can be damaged resulting in the loss of visual field. Loss of visual field is the hallmark symptom associated with glaucoma.
Prostaglandins, which are metabolite derivatives of arachidonic acid, have recently been pursued for possible efficacy in treating glaucoma and lowering IOP. The arachidonic acid cascade is initiated by the conversion of arachidonic acid to prostaglandin G2 and subsequent conversion to prostaglandin H2. Other naturally occurring prostaglandins are derivatives of prostaglandin H2. A number of different types of prostaglandins have been discovered including A, B, D, E, F and I-Series prostaglandins. Of interest in the present invention are combinations of compounds which exhibit IOP lowering mechanisms similar to that of PGF2xcex1, formula (I): 
The relationship between receptor activation by PGF2xcex1 and IOP lowering is not well understood. It is believed that FP receptor activation by PGF2xcex1 leads to increased outflow of aqueous humor. Regardless of mechanism, PGF2xcex1 and analogs have been shown to lower IOP (Giuffre, The Effects of Prostaglandin F2xcex1 the Human Eye, Graefe""s Archive Ophthalmology, volume 222, pages 139-141 (1985); and Kerstetter et al., Prostaglandin F2xcex1-1-Isopropylester Lowers Intraocular Pressure Without Decreasing Aqueous Humor Flow, American Journal of Ophthalmology, volume 105, pages 30-34 (1988). Thus, it has been of interest in the field to develop synthetic PGF2xcex1 analogs with IOP lowering efficacy.
Synthetic PGF2xcex1-type analogs have been pursued in the art (Graefe""s Archive Ophthalmology, volume 229, pages 411-413 (1991). Though PGF2xcex1-type molecules lower IOP, these types of molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects include an initial increase in IOP, breakdown of the blood aqueous barrier and conjunctival hyperemia (Alm, The Potential of Prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology, volume 4, No. 11, pages 44-50 (1993). The binding of PGF analogs with the FP receptor may lead to IOP lowering effects, but with fewer or diminished side effects compared to those elicited by the above mentioned PGF2xcex1-type analogs.
Attempts have been made by Stjernschantz et al. (U.S. Pat. No. 5,422,368), Woodward et al., (U.S. Pat. No. 5,093,329), Chan et al. (WO 92/08465) and Ueno et al. (U.S. Pat. No. 5,151,444) to use structural analogs and derivatives of prostaglandins to reduce selectively or to eliminate altogether the side effects while maintaining the IOP-lowering effect. The contents of the foregoing U.S. patents are by this reference incorporated herein. Commonly assigned U.S. Pat. Nos. 5,510,383; 5,627,209; 5,665,773; 5,721,273; 5,698,733; 5,807,892; 5,814,660; 5,866,602; 5,994,397; 6,025,392; and 6,169,111; and 6,172,109 are also by this reference incorporated herein.
Even such modified prostaglandins, however, still often exhibit undesirable side effects. Latanoprost, for example (commercially available from Pharmacia, Inc.) is generally not excessively hyperemic, but it is known to cause iridial hyperpigmentation, as well as darkening of the eyelids and lashes in some patients (secondary side effects). Clark, xe2x80x9cCurrent trends in antiglaucoma therapy,xe2x80x9d Emerging Drugs, 4:333-353 (1999). There remains a need, therefore, for a relatively side effect free prostaglandin-based therapy.
Use of the non-steroidal anti-inflammatory agents diclofenac sodium and fluorometholone in concurrent administration with the prostaglandin analog, latanoprost has been suggested to reduce the amount of flare and cystoid macular edema associated with the use of the prostaglandin analog in glaucoma therapy. Miyake et al., xe2x80x9cLatanoprost accelerates disruption of blood-aqueous barrier and the incidence of angiographic cystoid macular edema in early postoperative pseudophakis,xe2x80x9d Arch. Ophthl, 117(1):34-40 (1999). Commonly assigned U.S. Pat. Nos. 5,607,966; 5,750,564; and 5,607,966, which are by this reference incorporated herein, disclose non-steroidal anti-inflammatory agents useful in the treatment of ocular inflammation.
Certain non-steroidal cyclooxygenase inhibitors and their pharmaceutical formulations are useful for treating GLC1A glaucoma. The invention is also directed to methods for controlling GLC1A glaucoma using the non-steroidal cyclooxygenase inhibitors. A further aspect of the invention lies in the discovery that these non-steroidal anti-inflammatory agents and other prostaglandin synthesis inhibitors may be used in combination with prostaglandin analogs to treat glaucoma with reduced side effects.